European J of Heart Fail - 2024 - Zande - Diuretics in Pregnancy Data From The ESC Registry of Pregnancy and Cardiac

European Journal of Heart Failure (2024) RESEARCH ARTICLE
doi:10.1002/ejhf.3301
Diuretics in pregnancy: Data from the ESC

Registry of Pregnancy and Cardiac disease
(ROPAC)
Johanna A. van der Zande1,2, Matthias Greutmann3, Daniel Tobler4,
Karishma P. Ramlakhan1, Jerome M. J. Cornette2, Magalie Ladouceur5,
Nicholas Collins6, Dawn Adamson7, Vijaya P. Paruchuri8, Roger Hall9,
Mark R. Johnson10, and Jolien W. Roos-Hesselink1*, on behalf of the ROPAC
Investigators Group†
1 Department of Cardiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; 2 Department of Obstetrics and Fetal Medicine, Erasmus
MC – Sophia Children’s Hospital, University Medical Center Rotterdam, Rotterdam, The Netherlands; 3 Department of Cardiology, University Heart Center, University of Zurich,
Zurich, Switzerland; 4 Department of Cardiology, University of Basel, Basel, Switzerland; 5 Department of Cardiology, Georges-Pompidou European Hospital, Paris, France;
6 Department of Cardiology, John Hunter Hospital, New Lambton, NSW, Australia; 7 Department of Cardiology, University Hospital of Coventry and Warwickshire, West
Midlands, UK; 8 Department of Cardiology, Auburn Heart Institute, Auburn, NY, USA; 9 Department of Cardiology, University of East Anglia, Norwich, UK; and 10 Department of
Obstetric Medicine, Imperial College London, Kensington, London, UK
Received 15 January 2024; revised 24 April 2024; accepted 29 April 2024
Aims Data on diuretic use in pregnancy are limited and inconsistent, and consequently it remains unclear whether they can
be used safely. Our study aims to evaluate the perinatal outcomes after in-utero diuretic exposure.
.....................................................................................................................................................................
Methods The Registry Of Pregnancy And Cardiac disease (ROPAC) is a prospective, global registry of pregnancies in women
and results with heart disease. Outcomes were compared between women who used diuretics during pregnancy versus those
who did not. Multivariable regression analysis was used to assess the impact of diuretic use on the occurrence of
congenital anomalies and foetal growth. Diuretics were used in 382 (6.7%) of the 5739 ROPAC pregnancies, most
often furosemide (86%). Age >35 years (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.2–2.0), other cardiac
medication use (OR 5.4, 95% CI 4.2–6.9), signs of heart failure (OR 1.7, 95% CI 1.2–2.2), estimated left ventricular
ejection fraction <40% (OR 2.9, 95% CI 2.0–4.2), New York Heart Association class >II (OR 3.4, 95% CI 2.3–5.1),
valvular heart disease (OR 6.3, 95% CI 4.7–8.3) and cardiomyopathy (OR 3.9, 95% CI 2.6–5.7) were associated with
diuretic use during pregnancy. In multivariable analysis, diuretic use during the first trimester was not significantly
associated with foetal or neonatal congenital anomalies (OR 1.3, 95% CI 0.7–2.6), and diuretic use during pregnancy
was also not significantly associated with small for gestational age (OR 1.4, 95% CI 1.0–1.9).
.....................................................................................................................................................................
Conclusions Our study does not conclusively establish an association between diuretic use during pregnancy and adverse foetal
outcomes. Given these findings, it is essential to assess the risk–benefit ratio on an individual basis to guide clinical
..........................................................................................................
decisions.
*Corresponding author. Department of Cardiology, Erasmus MC, Room RG-435, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. Tel: +31 10 7032432,
Email: j.roos@erasmusmc.nl
† Listed in online supplementary Appendix S1.
© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and
reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
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2 J.A. van der Zande et al.
Graphical Abstract
Outcomes of the Registry of Pregnancy and Cardiac disease (ROPAC) regarding diuretic use during pregnancy. Data in n (%) unless otherwise
specified. CI, confidence interval; LMIC, low-or-middle-income country; LVEF, left ventricular ejection fraction; MACE, major adverse cardiac event
(combined endpoint of maternal mortality, heart failure, arrhythmia, endocarditis, thromboembolic event and dissection); mWHO, modified World
Health Organization; NYHA, New York Health Association; OR, odds ratio. *p < 0.05.
..........................................................................................................
Keywords Diuretics • Medication • Pregnancy • Counselling • Cardiovascular disease • Heart failure
Introduction metabolism and glomerular filtration rate.6,7 Diuretics are a class

.......................................
of medication that includes thiazide diuretics, loop diuretics, and

Cardiovascular disease is an important cause of maternal mor- potassium-sparing diuretics, which are frequently used in patients
tality and morbidity worldwide.1,2 Because of the increasing life with hypertensive disorders, heart failure and other conditions
expectancy due to advances in surgical and clinical management, a associated with volume overload.8–10 Through their effects on
rising number of women with congenital heart disease are reach- sodium and water balance, diuretics decrease plasma volume and
ing childbearing age and become pregnant.3,4 Additionally, major venous pressure.11,12 Because of this mechanism, it can be theo-
cardiovascular risk factors such as advanced maternal age, obe- rized that diuretics also have an impact on the placental perfusion
sity, hypertension, smoking and diabetes mellitus are increasingly when used during pregnancy and thereby may affect foetal growth.
prevalent among pregnant women.5 Therefore, it seems likely that However, data on diuretic use during pregnancy are limited and
medication use for the treatment of cardiovascular diseases will studies show varying results on foetal and neonatal outcomes.13–16
increase over time. During pregnancy, pharmacokinetic changes Therefore, diuretics are not routinely recommended during
occur due to an increase in total body water and changes in hepatic pregnancy, but are often needed to prevent overload in heart failure
Diuretics in pregnancy 3
and valvular heart disease. Our study aims to define the profile of as mean values with standard deviation when normally distributed,
........................................................................................................................................................................
women with heart disease using diuretics during pregnancy and to or as median with interquartile range if skewed. Unpaired t-tests or
evaluate the perinatal outcomes after in-utero diuretic exposure. one-way ANOVA were used to compare normally distributed contin-
uous data. The Mann–Whitney U test was used to compare differences
between continuous data, which were not normally distributed. Multi-
Methods ple imputation was used to handle missing values, reported in the figure
or table legends if applicable. A two-sided p-value <0.05 was consid-
The Registry Of Pregnancy And Cardiac disease (ROPAC) is a ered significant for all analyses. All statistical tests and analyses were
prospective, worldwide, observational registry of pregnant patients performed using IBM SPSS Statistics version 28.0.
with structural heart disease, including congenital and valvular heart Pre-pregnancy baseline characteristics and maternal and perinatal
disease, prosthetic heart valves, cardiomyopathy, ischaemic heart outcomes were compared between women who used diuretics during
disease, aortopathy and pulmonary arterial hypertension. ROPAC was pregnancy and those who did not. We performed a logistic regression
initiated in 2007 jointly by the European Society of Cardiology (ESC) analysis with backward selection to identify key features associated
working groups on congenital heart disease and valvular heart disease with diuretic use during pregnancy. A subanalysis was performed in
and is embedded in the EURObservational Research Programme of which characteristics and outcomes were compared between women
the ESC. For this analysis, pregnancies in women using diuretics during who used diuretics in the first trimester and those who did not use
pregnancy who were included in the ROPAC from 2007 up to 2018 diuretics during pregnancy.
were selected. The study protocol with a detailed description of the We performed a multivariable logistic regression analysis with back-
study design and ethical approval has been published previously.17 ward selection to explore the association between diuretic use during
Participating centres managed the approvals of national or regional pregnancy and small for gestational age. In the full model, we included
ethics committees or Institutional Review Boards, according to local the baseline characteristics with a p-value < 0.1 in the univariable anal-
regulations. ysis, the variables that had been identified in previous studies to have an
impact on birth weight (maternal age, BMI, LMIC, twin pregnancy and
smoking) and maternal cardiac diagnosis. In addition, we performed
Outcomes and definitions a multivariable logistic regression analysis with backward selection to
Pre-pregnancy baseline characteristics included age, body mass index explore the association between diuretic use in the first trimester and
(BMI), nulliparity, living in a low-or-middle-income country (LMIC) foetal and neonatal congenital anomalies. In this full model we included
(based on the International Monetary Fund classification), smoking, the baseline characteristics with a p-value < 0.1 in the univariable anal-
hypertension, diabetes mellitus, electrocardiogram rhythm, signs of ysis, variables that had been identified in previous studies to be a risk
heart failure, estimated left ventricular ejection fraction (LVEF) below factor for foetal and neonatal congenital anomalies (maternal age, twin
40%, New York Heart Association (NYHA) class >II, prior car- pregnancy, smoking, diabetes mellitus) and maternal cardiac diagnosis.
diac intervention, pre-pregnancy cardiac medication use and diagnosis Lastly, we performed sensitivity analyses stratified by country income
details. Diuretic use during pregnancy was defined as diuretic use at any level, based on the International Monetary Fund classification, for small
point during pregnancy, excluding use only during delivery or only prior for gestational age and congenital anomalies.
to pregnancy, whereas diuretic use in the first trimester was defined
as diuretic use at least during the first trimester. The exact indication
for medication use was not specifically documented. A major adverse Results
cardiac event (MACE) was defined as a combined endpoint of mater-
nal mortality, heart failure, arrhythmia, endocarditis, thromboembolic Baseline characteristics
event or aortic dissection. Heart failure was defined according to
Diuretics were used in 382 (6.7%) of the 5739 ROPAC pregnancies
the ESC guidelines,18 and heart failure episodes were only registered
(Figure 1). Furosemide was by far the most frequently used diuretic
when new treatment, change of treatment or hospital admission was
required. New-onset heart failure was defined as the occurrence of (86%) (Figure 2). The most common cardiac diagnosis of women
heart failure in women without a history of heart failure. The end- with diuretic use during pregnancy was valvular heart disease
point of foetal and neonatal congenital anomalies were combined as (59.4%), followed by cardiomyopathy (20.4%), congenital heart
a composite of the incidence of foetal or neonatal congenital anoma- disease (17%), pulmonary hypertension (2.1%), ischaemic heart
lies, either leading to including termination of pregnancy or birth with disease (0.8%) and aortopathy (0.3%) (Table 1). Rheumatic valvular
and confirmed neonatal congenital disease. Stillbirth was defined as disease (25.5% vs. 4.2%, p < 0.001) and endocarditis (18.4% vs.
foetal death beyond 20 weeks of pregnancy and neonatal mortality as 7.1%, p = 0.016) were predominantly associated with diuretic use.
death of a live-born baby within the first month of life. Preterm birth Compared to women without diuretic use, women who used
was subdivided into extremely preterm (≥24 weeks up to 28 weeks of diuretics during pregnancy were slightly older (30.9 vs. 29.4 years;
gestation), very preterm (≥28 weeks up to 32 weeks of gestation) and
p < 0.001), had a higher BMI (25.3 vs. 23.9 kg/m2 ; p < 0.001),
moderate to late preterm (≥32 weeks up to 37 weeks of gestation),
were more likely to live in an LMIC (63.1% vs. 38.1%; p < 0.001),
according to the definition of the World Health Organization (WHO).
Small for gestational age was defined as birth weight <10th percentile,
and more likely to have chronic hypertension (9.9% vs. 6.4%;
taking into account regional differences in foetal weight. p = 0.007), atrial fibrillation/flutter (7.1% vs. 1.5%; p < 0.001),
signs of heart failure (27.2% vs. 9.2%; p < 0.001) or an estimated
LVEF <40% (19.9% vs. 3.3%; p < 0.001) (Table 1). Women using
Statistical analysis diuretics during pregnancy more commonly had used diuretics
Categorical data are presented as frequencies (numbers) and percent- pre-pregnancy (45.3% vs. 0.8%; p < 0.001) and in addition were
ages and were compared using 𝜒 2 tests. Continuous data are presented more likely to also have used other types of cardiac medication
Figure 1 Diuretic use before, during and after pregnancy. Diuretics were used in 6.7% of the 5739 ROPAC pregnancies.
Figure 2 Type of diuretic. In five pregnancies, furosemide was switched during pregnancy or vice versa.
before pregnancy, such as beta-blockers (33.0% vs. 8.2%; p < 0.001) belonging to mWHO risk class IV, in 72.9% (86/118) the cardiac
.................
and angiotensin-converting enzyme inhibitors (12.0% vs. 2.1%; condition was known pre-pregnancy, but only 48.9% (42/86) of
p < 0.001). Women who used diuretics during pregnancy were these women had documented pre-pregnancy counselling about
more often classified in modified WHO (mWHO) risk class IV, the maternal and obstetric risks of pregnancy. Age above 35 years
compared to those who did not (30.9% vs. 5.4%; p < 0.001). Of the (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.2–2.0), other
118 pregnancies in women using diuretics during pregnancy and cardiac medication use (OR 5.4, 95% CI 4.2–6.9), signs of heart
Table 1 Baseline pre-pregnancy characteristics of women with structural heart disease with diuretic use during
pregnancy or during the first trimester, versus women with structural heart disease without diuretic use during
pregnancy
No diuretic use Diuretic use p-valuea Diuretic use during p-valueb

during pregnancy during pregnancy first trimester
(n = 5357) (n = 382) (n = 191)
...........................................................................................................................................
Diagnosis details
Congenital heart disease 3230 (60.3) 65 (17.0) <0.001 28 (14.7) <0.001
Valvular heart disease 1422 (26.5) 227 (59.4) <0.001 113 (59.2) <0.001
Cardiomyopathy 360 (6.7) 78 (20.4) <0.001 43 (22.5) <0.001
Aortopathy 216 (4.0) 1 (0.3) <0.001 1 (0.5) 0.014
Ischaemic heart disease 92 (1.7) 3 (0.8) 0.168 3 (1.6) 0.878
Pulmonary hypertension 37 (0.7) 8 (2.1) 0.003 3 (1.6) 0.158
mWHO I 1165 (21.7) 20 (5.2) <0.001 9 (4.7) <0.001
mWHO II 811 (15.1) 17 (4.5) <0.001 6 (3.1) <0.001
mWHO II–III 2505 (46.8) 193 (50.5) 0.155 92 (48.2) 0.702
mWHO III 563 (10.5) 30 (7.9) 0.099 20 (10.5) 0.986
mWHO IV 289 (5.4) 118 (30.9) <0.001 62 (32.5) <0.001
Pre-pregnancy characteristics
Age, years, mean ± SD 29.4 ± 5.6 30.9 ± 5.8 <0.001 30.7 ± 5.7 0.006
BMI, kg/m2 , median (Q1–Q3) 23.9 (21.5–27.5) 25.3 (22.1–29.4) <0.001 26.2 (22.8–30.0) <0.001
Nulliparity 2462 (46.0) 111 (29.1) <0.001 38 (19.9) <0.001
LMIC 2040 (38.1) 241 (63.1) <0.001 137 (71.7) <0.001
Current smoker 209 (3.9) 19 (5.0) 0.413 6 (3.1) 0.488
Chronic hypertension 342 (6.4) 38 (9.9) 0.007 23 (12.0) 0.002
Diabetes mellitus 81 (1.5) 9 (2.4) 0.220 6 (3.1) 0.086
Atrial fibrillation/flutter 79 (1.5) 27 (7.1) <0.001 20 (10.5) <0.001
Signs of heart failure 492 (9.2) 104 (27.2) <0.001 55 (28.8) <0.001
Estimated LVEF <40% 177 (3.3) 76 (19.9) <0.001 51 (26.7) <0.001
NYHA class >II 143 (2.7) 61 (16.0) <0.001 31 (16.2) <0.001
Prior cardiac intervention 3019 (56.4) 141 (36.9) <0.001 77 (40.3) <0.001
Pre-pregnancy cardiac medication use
Diuretics 44 (0.8) 173 (45.3) <0.001 164 (85.9) <0.001
Beta-blockers 437 (8.2) 126 (33.0) <0.001 92 (48.2) <0.001
ACE-inhibitors 111 (2.1) 46 (12.0) <0.001 35 (18.3) <0.001
Other cardiac medication 150 (2.8) 67 (17.5) <0.001 59 (30.9) <0.001
Anticoagulation 549 (10.2) 85 (22.3) <0.001 59 (30.9) <0.001
Data are n (%) unless otherwise specified.

ACE, angiotensin-converting enzyme; BMI, body mass index; LMIC, low-or-middle-income country; LVEF, left ventricular ejection fraction; mWHO, modified World Health
Organization; NYHA, New York Heart Association; Q1–Q3, interquartile range; SD, standard deviation.
a Diuretic use during pregnancy compared to no diuretic use during pregnancy.
b Diuretic use during the first trimester compared to no diuretic use during pregnancy.
failure (OR 1.7, 95% CI 1.2–2.2), estimated LVEF <40% (OR (excluding women with deterioration of pre-existing heart failure),
......................................
2.9, 95% CI 2.0–4.2), NYHA class >II (OR 3.4, 95% CI 2.3–5.1), women with new-onset heart failure more often had a multiple
valvular heart disease (OR 6.3, 95% CI 4.7–8.3) and cardiomy- pregnancy (6.1% vs. 0%; p < 0.001) and were commonly from a
opathy (OR 3.9, 95% CI 2.6–5.7) were independently associated high-income country (50.5% vs. 35.9%; p = 0.014).
with diuretic use during pregnancy (online supplementary Table
Appendix S1).
Perinatal outcomes
A comparison of obstetric and perinatal outcomes of pregnancies
Maternal outcomes with and without any diuretic exposure is reported in Table 2.
Major adverse cardiac events were more frequent in women who Termination of pregnancy was more frequent in pregnancies with
used diuretics during pregnancy (50.3% vs. 13.1%; p < 0.001), diuretic exposure (5.0% vs. 0.9%; p < 0.001), mainly for maternal
especially heart failure (45.3% vs. 8.2%; p < 0.001) (Table 2). health concerns (84.2%) and less due to foetal congenital anoma-
Compared to women without new-onset heart failure episodes lies (15.8%). Heart failure was the most reported reason for
Table 2 Pregnancy outcomes in women with structural heart disease with diuretic use during pregnancy or during
the first trimester, versus women with structural heart disease without diuretic use during pregnancy
No diuretic Diuretic use p-valuea Diuretic use p-valueb

use during during during first
pregnancy pregnancy trimester
(n = 5357) (n = 382) (n = 191)
...........................................................................................................................................
Maternal cardiac outcomes
MACE 703 (13.1) 192 (50.3) <0.001 73 (38.2) <0.001
Maternal mortalityc 35 (0.7) 5 (1.3) 0.137 3 (1.6) 0.131
Heart failure 438 (8.2) 173 (45.3) <0.001 59 (30.9) <0.001
New-onset heart failure 248 (4.6) 110 (28.8) <0.001 32 (16.8) <0.001
Arrhythmia 155 (2.9) 26 (6.8) <0.001 13 (6.8) 0.002
Supraventricular 79 (1.5) 16 (4.2) <0.001 9 (4.7) <0.001
Ventricular 79 (1.5) 11 (2.9) 0.033 4 (2.1) 0.488
Endocarditis 32 (0.6) 1 (0.3) 0.402 0 (0) 0.284
Thromboembolic event 75 (1.4) 12 (3.1) 0.007 5 (2.6) 0.165
Dissection 5 (0.1) 0 (0) 0.550 0 (0) 0.673
Hospital admission for cardiac reason 611 (11.4) 147 (38.5) <0.001 61 (31.9) <0.001
Obstetric and foetal outcomes
Reported miscarriage 194 (3.6) 20 (5.2) 0.108 18 (9.4) <0.001
Therapeutic termination of pregnancy 49 (0.9) 19 (5.0) <0.001 17 (8.9) <0.001
For foetal anomalies 13 (0.2) 2 (0.5) 0.299 2 (1.0) 0.035
For maternal health concerns 32 (0.6) 16 (4.2) <0.001 14 (7.3) <0.001
Pregnancy-induced hypertension 139 (2.6) 11 (2.9) 0.765 2 (1.0) 0.177
Pre-eclampsia and HELLP syndrome 150 (2.8) 9 (2.4) 0.583 2 (1.0) 0.139
Gestational diabetes mellitus 148 (2.8) 12 (3.1) 0.681 4 (2.1) 0.568
Stillbirth 65 (1.2) 7 (1.8) 0.294 5 (2.6) 0.087
Delivery
Gestational age at delivery, weeks, median (Q1–Q3) 38.7 (37.4–39.7) 37.9 (36.0–39.0) <0.001 38.0 (36.1–39.0) <0.001
Caesarean section 2442 (45.6) 239 (62.6) <0.001 115 (60.2) <0.001
Planned Caesarean section 1730 (32.3) 185 (48.4) <0.001 24 (12.6) 0.771
For cardiac reason 634 (11.8) 96 (25.1) <0.001 10 (5.2) 0.004
Emergency Caesarean section 712 (13.3) 54 (14.1) 0.639 91 (47.6) <0.001
For cardiac reason 112 (2.1) 20 (5.2) <0.001 43 (22.5) <0.001
Postpartum haemorrhage 148 (2.8) 22 (5.8) 0.001 11 (5.8) 0.015
Neonatal outcomes
Preterm birth 789 (14.7) 111 (29.1) <0.001 45 (23.6) <0.001
Extremely preterm 31 (0.6) 4 (1.0) 0.256 3 (1.6) 0.074
Very preterm 111 (2.1) 18 (4.7) <0.001 5 (2.6) 0.604
Moderate to late preterm 647 (12.1) 89 (23.3) <0.001 37 (19.4) 0.003
Apgar score <7 at 5 min 355 (6.6) 42 (11.0) 0.001 15 (7.9) 0.504
Mean birth weight, g, mean ± SD 3005 ± 625 2632 ± 664 <0.001 2664 ± 656 <0.001
Birth weight <2500 g 561 (10.5) 112 (29.3) <0.001 43 (22.5) <0.001
Small for gestational age 527 (9.8) 57 (14.9) 0.001 25 (13.1) 0.128
Neonatal congenital disease 263 (4.9) 20 (5.2) 0.776 9 (4.7) 0.901
Neonatal congenital heart disease 145 (2.7) 11 (2.9) 0.841 6 (3.1) 0.717
Other neonatal congenital disease 118 (2.2) 9 (2.3) 0.973 3 (1.6) 0.567
Neonatal mortality 29 (0.5) 4 (1.0) 0.207 2 (1.0) 0.357
Total foetal and neonatal congenital anomalies 276 (5.2) 22 (5.8) 0.605 11 (5.8) 0.710
Data are n (%) unless otherwise specified.

HELLP, haemolysis, elevated liver enzymes and low platelet syndrome; MACE, major adverse cardiac event; Q1–Q3, interquartile range; SD, standard deviation.
a Diuretic use during pregnancy compared to no diuretic use during pregnancy.
b Diuretic use during the first trimester compared to no diuretic use during pregnancy.
c Maternal mortality up to 6 months postpartum.
Table 3 Univariable and multivariable logistic regression with backward selection for small for gestational age
Univariable Multivariable (final model)

............................................ ..................................................
OR 95% CI p-value OR 95% CI p-value
...........................................................................................................................................
Diuretic use during pregnancya 1.61 1.20–2016 0.002 1.35 0.97–1.89 0.077
Age >35 yearsa 1.08 0.85–1.36 0.537
Nulliparity 1.08 0.91–1.29 0.366
Obesity (BMI >30 kg/m2 )a 0.79 0.58–1.08 0.146 0.69 0.50–0.95 0.023
Underweight (BMI <18 kg/m2 )a 1.69 0.97–2.96 0.065
LMICa 1.02 0.86–1.22 0.797
Twin pregnancya 3.57 2.27–5.62 <0.001 3.81 2.40–6.03 <0.001
Other cardiac medication usea 1.61 1.28–2.02 <0.001 1.36 1.05–1.75 0.019
Current smokera 1.45 1.00–2.09 0.052 1.39 0.95–2.03 0.086
Chronic hypertensiona 1.32 1.21–2.18 0.001 1.35 0.99–1.84 0.061
Diabetes mellitus 1.09 0.56–2.12 0.798
Atrial fibrillation/flutter 1.35 0.77–2.39 0.299
Signs of heart failurea 1.65 1.29–2.10 <0.001 1.45 1.10–1.91 0.009
Estimated LVEF <40%a 1.99 1.42–2.77 <0.001 1.57 1.08–2.30 0.019
NYHA class >IIa 2.16 1.51–3.10 <0.001 1.60 1.06–2.41 0.025
mWHO >IIa 1.30 1.08–1.57 0.005
CHDa 1.03 0.87–1.22 0.744 0.78 0.56–1.08 0.140
VHDa 0.76 0.62–0.93 0.007 0.55 0.39–0.79 0.001
CMPa 1.24 0.92–1.67 0.166 0.63 0.41–0.97 0.035
After multiple imputation for age (9.5%), BMI (36.2%), parity (0.3%), smoking (14.2%), prior hypertension (1.7%), prior diabetes (2.3%), prior heart failure (1.4%) and gestational
diabetes (1.2%).
BMI, body mass index; CHD, congenital heart disease; CI, confidence interval; CMP, cardiomyopathy; LMIC, low-or-middle-income country; LVEF, left ventricular ejection
fraction; mWHO, modified World Health Organization; NYHA, New York Heart Association; OR, odds ratio; VHD, valvular heart disease.
a Backward selection: full model.
therapeutic termination due to maternal health concerns. Women furosemide of 40 mg or more (n = 201), including preterm birth
............................................................................
treated with diuretics delivered more frequently by Caesarean and the different preterm birth stages.
section (62.6% vs. 45.6%; p < 0.001), of which most were planned
(77.4%). In women with diuretic exposure during pregnancy,
preterm birth (29.1% vs. 14.7%; p < 0.001), low Apgar score Diuretic use in the first trimester
(11.0% vs. 6.6%; p = 0.001) and small for gestational age (14.9% vs. The baseline characteristics and pregnancy outcomes of women
9.8%; p = 0.001) were more common. In the multivariable analysis, using diuretics during the first trimester versus women without
diuretic use was, however, not associated with small for gestational diuretic use during pregnancy are presented in Tables 1 and 2. No
age (OR 1.4, 95% CI 1.0–1.9) (Table 3). In contrast, twin pregnancy difference was found in the occurrence of the composite outcome
(OR 3.8, 95% CI 2.4–6.0), other cardiac medication use (OR 1.4, (including foetal and neonatal congenital anomalies) in women using
95% CI 1.1–1.8), signs of heart failure (OR 1.5, 95% CI 1.1–1.9), diuretics in the first trimester versus women without any diuretic
LVEF <40% (OR 1.6, 95% CI 1.1–2.3) and NYHA class >II (OR use during pregnancy (5.8% vs. 5.2%; p = 0.710). In addition, in the
1.6, 95% CI 1.1–2.4) were associated with small for gestational multivariable analysis, diuretic use during the first trimester was still
age. The outcomes of the multivariable logistic regression analysis not associated with foetal and neonatal congenital anomalies (OR
for small for gestational age stratified by country are presented in 1.3, 95% CI 0.7–2.6) (Table 4). The outcomes of the multivariable
online supplementary Table S2. In addition, when diuretics were logistic regression analysis for congenital anomalies stratified by
used in all trimesters, indicating long-term exposure, no difference country are presented in online supplementary Table S4.
was found in the incidence of small for gestational age infants
(13.6% vs. 9.8%; p = 0.110). The perinatal outcomes comparing
women who used furosemide during pregnancy versus women
who used any other type of diuretic (with the exception of the
Discussion
women who used a combination of different diuretics or who Diuretics were used in 7% of the ROPAC pregnancies, and the most
switched during pregnancy) are presented in online supplementary commonly used agent was furosemide. The use of diuretics during
Table S3. We found no differences in perinatal outcomes between pregnancy was associated with advanced mWHO categories and
the women who used a daily dose below 40 mg furosemide more MACE during pregnancy compared to the women who did
(n = 131) compared to the women who used a daily dose of not used diuretics. However, despite this no difference in maternal
Table 4 Univariable and multivariable logistic regression with backward selection for foetal or neonatal congenital
anomalies
Univariable Multivariable (final model)

........................................... .................................................
OR 95% CI p-value OR 95% CI p-value
...........................................................................................................................................
Diuretic use during 1st trimestera 1.12 0.60–2.08 0.720 1.30 0.66–2.55 0.444
Age >35 yearsa 1.19 0.87–1.61 0.277
Nulliparitya 1.27 1.01–1.61 0.043 1.21 0.95–1.53 0.124
Obesity (BMI >30 kg/m2 ) 0.92 0.61–1.38 0.684
Underweight (BMI <18 kg/m2 ) 1.48 0.68–3.23 0.324
LMICa 0.79 0.62-1.01 0.061 0.97 0.75–1.26 0.840
Twin pregnancya 0.79 0.29–2.17 0.649
Other cardiac medication usea 1.38 1.00–1.89 0.048 1.33 0.94–1.90 0.109
Current smokera 1.13 0.64–2.01 0.665
Chronic hypertension 0.95 0.59–1.53 0.828
Diabetes mellitusa 1.64 0.73–3.66 0.229 1.75 0.86–3.58 0.126
Atrial fibrillation/flutter 0.35 0.09–1.41 0.139
Signs of heart failure 0.96 0.65–1.41 0.816
Estimated LVEF <40% 0.66 0.34–1.30 0.234
NYHA class >II 0.84 0.43–1.65 0.609
mWHO >IIa 0.73 0.58–0.93 0.009
CHDa 1.45 1.14–1.86 0.003 0.57 0.37–0.86 0.007
VHDa 0.37 0.26–0.52 <0.001 0.25 0.15–0.41 <0.001
CMPa 1.22 0.81–1.83 0.341 0.62 0.36–1.05 0.077
After multiple imputation for age (9.5%), BMI (36.2%), parity (0.3%), smoking (14.2%), prior hypertension (1.7%), prior diabetes (2.3%), prior heart failure (1.4%) and gestational
diabetes (1.2%).
BMI, body mass index; CHD, congenital heart disease; CI, confidence interval; CMP, cardiomyopathy; LMIC, low-or-middle-income country; LVEF, left ventricular ejection
fraction; mWHO, modified World Health Organization; NYHA, New York Heart Association; OR, odds ratio; VHD, valvular heart disease.
a Backward selection: full model.
mortality was found. Importantly, diuretic use in the first trimester hypertension as the only indication for diuretic use, we recom-
............................................................................
was not associated with a higher incidence of congenital anomalies. mend to switch to nifedipine, methyldopa or possibly beta-blockers
Furthermore, we found no association of small for gestational age (except for atenolol because of the relatively high risk of foetal
and diuretic use during pregnancy (Graphical Abstract). growth restriction), in women planning a pregnancy or in early
pregnancy, simply because more foetal safety data on these antihy-
pertensive drugs are available.23,24 In women with other indications
Foetal safety for diuretic use, such as heart failure and other conditions with vol-
One of the biggest concerns in use of maternal medication during ume overload, diuretics, especially furosemide, can be continued.
pregnancy is that it may cause congenital anomalies in the foetus.
Given that foetal organogenesis mainly occurs in the first trimester
of pregnancy, drug exposure during this period is of particular con- Foetal growth
cern.19 In our study, no significant difference in the number of foetal A reduction in systemic vascular resistance leading to an increase
and neonatal congenital anomalies was found between women in plasma volume and cardiac output as from early in pregnancy
using diuretics during the first trimester and women who did not and continuing throughout its course are important physiological
use diuretics during pregnancy. This is in line with previous data.15 adaptive mechanisms that facilitate placentation and later placental
A previous study based on US Food and Drug Administration data function and perfusion.25,26 The placenta has no autoregulation,
from 1996 to 2000 reported that there was no foetal safety data which makes it preload-dependent. Haemodynamic maladaptation
for approximately half of the medications prescribed to pregnant is associated with hypertensive disorders of pregnancy and/or
women.20 This indicates the need for more studies on the safety foetal growth restriction.27 Theoretical concerns that diuretics
of medications prescribed to pregnant women. However, pregnant might impact placentation, placental function and perfusion and
women are typically excluded from clinical trials, consequently, thereby foetal growth are therefore legitimate. Women who use
we will depend on observational data provided by the current diuretics during pregnancy have a lesser increase in the plasma
study. Typically prescribed antihypertensive medications include volume usually seen during pregnancy.13 Sibai et al.13 showed a
labetalol, nifedipine and methyldopa, which are widely accepted minimal plasma volume expansion of 18% in pregnant women
as safe in pregnancy, based on observational data from registries with mild hypertension using diuretics, whereas pregnant women
and meta-analyses of small clinical trials.21,22 In women with with mild hypertension, who discontinued diuretics had a plasma
volume expansion of 52% throughout pregnancy. However, no pregnancies are less likely to have been completely included in
........................................................................................................................................................................
difference in perinatal outcomes were observed among the two the registry and therefore may be underrepresented. Therefore,
groups. In another study involving women with pre-eclampsia, no valid conclusion can be given on the association between
reduced plasma volumes were found compared to normal subjects, diuretic use in the first trimester and risk of miscarriage. We have
as well as more small for gestational age infants.28 Despite the no data on the duration of diuretic use, other than use during
fact that a causal relationship has not been established, these data the first, second, and/or third trimester. Furthermore, the indi-
have led to caution in prescribing diuretics during pregnancy. In cation for diuretic use was not available. Another limitation is the
our study, the number of small for gestational age infants was absence of detailed neonatal outcome data. Early case reports have
not different between women using diuretics at any time during described neonatal thrombocytopenia and jaundice in association
pregnancy and those women who did not use diuretics at any time with in-utero diuretic exposure.30–32 However, these complica-
during pregnancy. Additionally, when we only included the women tions have not been described since then, suggesting that these
who used diuretics during all trimesters, indicating long-term associations may be due to selected case reporting.33 Lastly, it
in-utero exposure, there was no difference in the number of small was not possible to compare the outcomes between the differ-
for gestational age infants. This suggests that overall cardiovascular ent types of diuretics, because the vast majority used furosemide.
function, if necessary supported by diuretics, is more important On the other hand, this reflects real-life clinical practice and
for cardiovascular adaptation to pregnancy, placental function and resulted in sufficient numbers to evaluate furosemide as safe during
foetal growth than the selective effect diuretics may have on foetal pregnancy.
growth by their effect on plasma volume. Indeed, a previous study,
which analysed the effect of diuretics on foetal growth, supports
these findings, and even documented a slightly higher mean birth Conclusions
weight of 113 g in neonates of women who used loop diuretics
Based on our data, furosemide can be used safely during preg-
during pregnancy and delivered at term compared to the group
nancy, but more data on foetal outcomes after in-utero exposure
without use of diuretics.15 Czeizel et al. also found an increased
to other types of diuretics are needed. When diuretics are only
birth weight in women who used furosemide during pregnancy.16
prescribed for hypertension, other antihypertensive agents, are
However, these results were not adjusted for confounders, such as
recommended as they have more safety data on foetal outcomes.
underlying disease, which could explain the contradictory findings.
When diuretics are prescribed for other cardiac indications, dis-
continuing of diuretics, especially furosemide, in pregnant women
Preconception counselling does not seem necessary. It is possible that overall cardiovascular
function, if necessary supported by diuretics, is more important
Women who used diuretics during pregnancy had more maternal
for maternal outcome, foetal growth and foetal outcome than the
cardiac complications, especially heart failure. Due to a high risk of
potential adverse diuretics may cause through reduced plasma vol-
maternal mortality and/or a very high risk of morbidity, pregnancy
ume expansion on theoretical grounds. Preconception counselling
is deemed contraindicated in women classified in mWHO class IV
allows for medication to be switched or stopped when warranted
and if pregnancy occurs, guidelines recommend that termination
and prevents unnecessary patient-initiated withdrawal of essential
should be discussed. Despite this, in 73% of the women in mWHO
treatments.
class IV the cardiac diagnosis was known before pregnancy, but
even less than half of them had documented pre-pregnancy coun-
selling. Preconception counselling is not only important to educate Supplementary Information
and inform women on the impact of pregnancy on their heart
disease and vice versa, but also to optimize their clinical condi- Additional supporting information may be found online in the
tion.29 Preconception counselling gives the opportunity to provide Supporting Information section at the end of the article.
appropriate advice to women about their medication, and prevent
women from quitting on their own initiative due to concerns about Acknowledgements
adverse effects on the foetus, which can also be dangerous for the EORP Oversight Committee, ROPAC Executive Committee. Data
women themselves. Discontinuing diuretics may even precipitate collection was conducted by the EORP department from the ESC
deterioration of the underlying cardiac condition. Based on our by Elin Folkesson Lefrancq as Project Officer; Viviane Missiamenou,
data, diuretics, especially furosemide, can be continued, without Gérard Gracia and Sébastien Authier as Data Managers. Overall
elevated risks for foetal congenital anomalies or small for gesta- activities were coordinated and supervised by Dr. Aldo P. Maggioni,
tional age. Scientific Coordinator.
Limitations Funding
Our study has several limitations. The ROPAC pregnancies were This work was supported by the ESC EORP. Funding from ‘Zabawas
enrolled by different physicians worldwide and selection bias Foundation’ and ‘De Hoop Foundation’ in addition to the support from
cannot be ruled out. We performed no further analysis on EORP is greatly acknowledged. Since the start of EORP, the following com-
early pregnancy complications, such as miscarriage, because these panies have supported the programme: Abbott Vascular Int. (2011–2021);
Amgen Cardiovascular (2009–2018); AstraZeneca (2014–2021); Bayer 14. Collins R, Yusuf S, Peto R. Overview of randomised trials of diuretics in
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AG (2009–2018); Boehringer Ingelheim (2009–2019); Boston Sci- pregnancy. Br Med J (Clin Res Ed) 1985;290:17–23. https://doi.org/10.1136/bmj
.290.6461.17
entific (2009–2012); The Bristol Myers Squibb and Pfizer Alliance
15. Olesen C, de Vries CS, Thrane N, MacDonald TM, Larsen H, Sørensen HT, et al.
(2011–2019); Daiichi Sankyo Europe GmbH (2011–2020); The Alliance Effect of diuretics on fetal growth: A drug effect or confounding by indication?
Daiichi Sankyo Europe GmbH and Eli Lilly and Company (2014–2017); Pooled Danish and Scottish cohort data. Br J Clin Pharmacol 2001;51:153–157.
Edwards (2016–2019); Gedeon Richter Plc. (2014–2016); Menarini Int. https://doi.org/10.1111/j.1365-2125.2001.01310.x
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European Journal of Heart Failure (2024) RESEARCH ARTICLE

Diuretics in pregnancy: Data from the ESC

Received 15 January 2024; revised 24 April 2024; accepted 29 April 2024

† Listed in online supplementary Appendix S1.

Introduction metabolism and glomerular filtration rate.6,7 Diuretics are a class

of medication that includes thiazide diuretics, loop diuretics, and

No diuretic use Diuretic use p-valuea Diuretic use during p-valueb

Data are n (%) unless otherwise specified.

No diuretic Diuretic use p-valuea Diuretic use p-valueb

Data are n (%) unless otherwise specified.

Univariable Multivariable (final model)

Univariable Multivariable (final model)

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